This project has been initiated in order to develop a team approach to clarifying the mechanisms by which tumors affect the skeleton and cause disastrous clinical consequences such as hypercalcemia, bone pain and susceptibility to fracture. It is our contention that tumors exert their effects via production of osteotropic factors. Recent studies by ourselves and others indicate that these factors are heterogeneous and their complete identification and characterization will require a broadly based approach involving investigators with expertise in widely disparate areas. The specific aims of this research are to identify the tumor products which affect bone cell function and lead to osteolytic metastiasis and hypercalcemia and to detemine how these factors interact with each other in causing bone destruction and hypercalcemia. Our plan is primarily to use in vitro techniques of cell culture to identify factors which affect bone cell function using sensitive bioassays for bone resorption. We intend to characterize the role of the tumor derived transforming growth factors, the PTH-like factors associated with hypercalcemia, and the family of osteoclast activating factors produced by hematologic malignancies. Since the expertise required to identify and clarify these heterogeneous factor will require the attention of investigators with different types of skills, a team approach will be used to unite a number of diverse approaches around the tightly focused goal of clarifying the mechanisms responsible for bone destruction in various tumor types. (P)